1. Gaucher Disease: Overview and Therapeutic Goals

2. Gaucher Disease: Overview  The most common lysosomal storage disease 1 Incidence: approximately 1 in 40,000 for non-Jewish populations 3  Caused by a deficiency of the enzyme glucocerebrosidase 1,2  The glycolipid glucocerebroside accumulates in lysosomes of macrophages 1,2  Lipid-filled Gaucher cells displace normal cells in 3 Bone marrow Spleen Liver Lungs CNS* * In neuronopathic subtypes only. 1. Grabowski GA. Lancet. 2008;372:1263–1271. 2. Futerman AH, et al. Nat Rev Mol Cell Biol. 2004;5:554–565. 3. Sidransky E, et al. Emedicine Web site. http://www.emedicine.medscape.com/article/944157-overview. Accessed February 12, 2010. CNS = central nervous system. © 2009 Rector and Visitors of the University of Virginia. Charles E. Hess, MD, and Lindsey Krstic, BA, RN (arrow indicates Gaucher cell)

3. Assessment of Disease Severity and Development of Treatment Goals in Type 1 Gaucher Disease

4. Gaucher Disease: Clinical Signs and Symptoms Grabowski GA. Lancet. 2008;372:1263–1271. Pulmonary involvement Progressive neurologic symptoms* Hepatosplenomegaly Skeletal involvement Thrombocytopenia and anemia * In neuronopathic subtypes only.

5. Assessing Disease Severity DomainAssessmentDisease Severity Score Index 0 123 Skeletal DomainBMIabsent/minimalmildintermediatesevere Mineral componentabsent/minimalmildintermediatesevere Osteonecrosisnonemedullary infarctionosteonecrosisprosthesis Fractureabsent+ Hematological DomainHemoglobin > 12 g/dL (male) > 11.5 g/dL (female)10–12 g/dL8–9.9 g/dL < 8 g/dL* (*) or need for blood transfusion WBC count> 4 x 10 9 /L2.5–4 x 10 9 /L< 2.5 x 10 9 /L< 1.9 x 10 9 /L Platelet count> 150 x 10 9 /L101–150 x 10 9 /L60–100 x 10 9 /L< 60 x 10 9 /L Bleeding time< 8 min> 8 min Biomarker DomainChitotriosidase< 600 nmol/mL x h 600–4,000 nmol/mL x h 4,001–15,000 nmol/mL x h> 15,000 nmol/mL x h CCL 18< 72 ng/mL72–236 ng/mL237–1,000 ng/mL> 1,000 ng/mL Visceral DomainSpleen no MR/US lesions no splenectomy volume < 5 N volume between 5–9 N splenectomy volume between 10–15 N MR/US lesions volume > 15 N Liver no hepatic disease volume < 1.25 N volume between 1.25–2.5 Nvolume > 2.5 Nhepatic disease Lung DomainPulmonary hypertensionabsentmoderatesevere Respiratory failureabsentmoderatesevere Neurological Domainno signs/symptoms peripheral neuropathy Parkinson’s disease/Parkinsonism Total

6. Therapeutic Goals  Developed by a group of physicians from around the world with clinical expertise in treating Gaucher patients (ICGG)  Areas targeted for treatment goal development Visceral organs  Liver volume  Spleen volume Hematological  Anemia  Thrombocytopenia Pulmonary  Interstitial lung disease  Pulmonary vascular disease  Time frames that are described are based on past experience with alglucerase/imiglucerase  These goals may be useful as benchmarks when evaluating treatment regimens Pastores GM, et al. Semin Hematol. 2004;41(4Suppl 5):4–14. Skeletal pathology  Bone pain/bone crises  Osteonecrosis and subchondral joint collapse  Bone mineral density Growth (pediatric population)  Growth patterns/puberty Functional health and well-being  Normal daily activities

7. Therapeutic Goals: Hepatosplenomegaly Hepatomegaly* Splenomegaly* Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14. PatientsGoal Time Frame All patients  Reduce liver volume to 1–1.5 times normal and maintain All patients  Reduce liver volume by 20–30%  Reduce liver volume by 30–40% Years 1 to 2 Years 3 to 5 PatientsGoalTime Frame All patients  Reduce spleen volume to ≤ 2 to 8 times normal and maintain All patients  Reduce spleen volume by 30–50%  Reduce spleen volume by 50–60% Year 1 Years 2 to 5 All patients  Alleviate symptoms due to splenomegaly: abdominal distension, early satiety, new splenic infarction  Eliminate hypersplenism *Please note regular assessments will be conducted.

8. Therapeutic Goals: Anemia* PatientsGoalTime Frame Adult female patients and children Hb ≥ 11.0 g/dLYears 1 to 2 Male patients > 12 years Hb ≥ 12.0 g/dLYears 1 to 2 All patients  Eliminate blood transfusion  Reduce fatigue  Maintain improved Hb levels Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14. *Please note regular assessments will be conducted.

9. Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14. PatientsGoalTime Frame All patients  Sufficient platelets to reduce bleedingYear 1 Splenectomized patients  Normalization of platelet countsYear 1 Intact spleen Moderate thrombocytopenia (> 60,000–< 120,000/mm 3 ) Severe thrombocytopenia (< 60,000/mm 3 )  Low-normal platelet counts  Continued increases but no normalization Year 2 Therapeutic Goals: Thrombocytopenia* *Please note regular assessments will be conducted.

10. Therapeutic Goals: Pulmonary Involvement* Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14. PatientsGoal Patients with overt, symptomatic pulmonary involvement**  Reverse hepatopulmonary syndrome and dependency on oxygen  Ameliorate pulmonary hypertension  Improve functional status and quality of life  Prevent rapid deterioration of pulmonary disease and sudden death All patients  Prevent pulmonary disease by timely initiation of treatment and avoidance of splenectomy ** Most patients in this group have had spleen removed. *Please note regular assessments will be conducted.

11. Therapeutic Goals: Bone Disease* Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14. PatientsGoalTime Frame All patients  Lessen or eliminate bone pain  Prevent bone crises  Prevent osteonecrosis and subchondral joint collapse 1 to 2 years Pediatric patients  Improve BMD  Attain normal or ideal peak skeletal mass  Increase cortical and trabecular BMD  Improve BMD  Increase trabecular BMD 2 years Adult patients *Please note regular assessments will be conducted. 3–5 years

12. Therapeutic Goals: Pediatric Growth and Functional Health and Well-being* Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14. Pediatric Growth PatientsGoalTime Frame Pediatric patients  Normalize growth such that patient achieves a normal height according to population standards Within 3 years Pediatric patients  Achieve normal onset of puberty Functional Health and Well-being Patients GoalTime Frame All patients  Improve or restore physical function for carrying out normal daily activities and fulfilling functional roles All patients  Improve scores from baseline of a validated quality-of-life instrument 2–3 years or less (depending on disease burden) *Please note regular assessments will be conducted.

13. A Comprehensive Management Plan  Defined specific management goals Act as a guide for managing physicians, consulting specialists, allied health personnel Educate patients and families Establish reasonable expectations  Most patients will have multiple therapeutic goals To be completed within an expected timeframe Maintained for life  Success depends on Comprehensive initial assessment of all potentially affected organs and systems Regular monitoring Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

14. Recommendations for Monitoring: Achieved vs Not Achieved Therapeutic Goals  Patients on Therapy: For those who are receiving therapy, the frequency of recommended evaluations is dependent on whether or not a particular patient has achieved his or her therapeutic goals Not Achieved Therapeutic Goals: Until the therapeutic goals have been met, it is advisable to have hemoglobin levels, platelet counts, and biochemical markers checked at least every 3 months. A thorough physical examination, as well as visceral and skeletal evaluations, should be completed annually Achieved Therapeutic Goals: Once a clear and sustainable response to treatment has been established, the recommended frequency for checking lab values, visceral response, and skeletal disease diminishes, allowing for routine monitoring every 12–24 months (at a minimum). However, a thorough physical examination should be conducted annually Weinreb NJ, et al. Semin Hematol. 2004;41(suppl 5):15–22.

15. The Therapeutic Goals MAP Tool   Designed as a point-of-care management tool by an international taskforce Provides a visual representation of patient status and therapeutic outcomes over time  The MAP tool can be adapted for different patient populations For pediatric patients, growth will be displayed as an additional domain For splenectomized patients, the splenomegaly domain is omitted  A biomarker domain can also be incorporated for chitotriosidase (CHITO) and chemokine (C-C motif) ligand 18 (CCL18)  Hard copy and electronic versions have been developed http://www.therapeuticgoalsmap.com/

16. Therapeutic Goals MAP Tool  (electronic) – Adult and Pediatric Version © Shire Pharmaceuticals Group, 2010. AdultPediatric

17. Therapeutic Goals MAP

18. Expanding Adoption of Therapeutic Goals May Assist With Benefit Patient Care Encourage and facilitate use of therapeutic goals in day-to-day clinical practice Novel, user-friendly, visual point-of-care assessment Many patients do not currently achieve all the guideline therapeutic goals 1 Standardize a goal-oriented approach, in tandem with regular monitoring, to optimize patient care 1. Weinreb NJ, et al. Am J Hematol. 2008;83:890–895. Help in the building of partnerships between physicians and patients

19. Therapeutic Goals MAP Tool – Summary  Allows physicians to collate clinical data over time and help guide management by tracking patient progress using therapeutic goal domains  Allows other specialists and allied healthcare professionals to closely follow patients’ progress  Importantly, by further engaging patients and families in the management process and enhancing their understanding of clinical outcomes, use of the MAP tool may create create a partnership in caring  For more information, please visit www.therapeuticgoalsmap.com or also contact a Shire Global Medical Affairs representativewww.therapeuticgoalsmap.com